During their replicative cycle, retroviruses frequently generate variants through the processes of point mutation or recombination. Such variants may exhibit different properties that alter their infectivity and/or pathogenicity. The major focus of this project is the study of the generation of retrovirus variants and their role in disease processes. Inbred mouse strains harbor a family of closely related endogenous retroviral sequences. Upon infection of these mice by retroviruses such as the ecotropic Friend erythroleukemia virus (F- MuLV) or Moloney lymphocytic leukemia virus (M-MuLV), the inoculated viruses undergo recombination with the endogenous retroviral sequences to generate new retroviruses. The recombinant viruses, termed polytropic MuLVs, exhibit an altered infectious host range and utilize a cell surface receptor distinct from the receptor utilized by ecotropic MuLVs. In several murineleukemias, polytropic MuLVs generated after inoculation of ecotropic MuLVs have been shown to be directly involved in leukemogenesis. Although there are 30 to 40 endogenous sequences in mice that could potentially recombine with ecotropic MuLVs to generate polytropic viruses, their participation in the recombination process is not random. We have found that different inoculated ecotropic viruses consistently generate different populations of polytropic viruses. Furthermore, we have found that a small region of the viral genome encoding the gene for the nucleocapsid protein strongly influences the choice of endogenous sequences that recombine with the ecotropic MuLVs to generate polytropic MuLVs.Infection of the host by retroviruses frequently results in mixed retrovirus infections. Mixed retrovirus infections are generated either by infection with a heterogeneous mixture of viruses or by genetic alterations which occur subsequent to infection. Prime examples of the latter are variants which arise by point mutation in HIV-infected individuals and the polytropic variants in mice that arise by recombination. Mixed infections by retroviruses with different properties can result in virus interactions that potentially could influence their spread and pathogenicity. Our initial studies of mixed retrovirus infection illustrated a stepwise mechanism for the induction of lymphocytic leukemia facilitated by viral interference and pseudotyping between ecotropic and polytropic MuLVs. Recently our studies of mixed retrovirus infection have focused on mice co- inoculated with mixtures of ecotropic and polytropic MuLVs. We have observed profound effects on the generation of new recombinant viruses, the infectious spread of the inoculated viruses and the pathology induced by virus infection. With different retrovirus combinations we have found the complete suppression of new polytropic MuLVs normally observed after ecotropic MuLV infection: the rapid induction of a neurological disease not observed after inoculation with either virus alone: the severe elevation of polytropic MuLV viremia and, with one virus combination, a substantial delay in the onset of leukemia induced by an ecotropic MuLV. - Retroviruses, Leukemia, Mice, neuropathology